The main objective of the proposed research is to understand the mechanisms by which estrogenic modulation of the cholinergic system facilitates spatial memory. The proposed studies uniquely address these issues in a series of three experiments using drug injections, a recently developed mouse cholinergic immunotoxin, and a knockout mouse lacking estrogen receptor alpha (ERa). The specific aims are as follows: 1) To determine whether estrogen facilitates spatial memory retention in mice through modulation of cholinergic function, 2) To examine whether destruction of basal forebrain cholinergic afferents to neocortex and hippocampus by a new mouse immunotoxin affects estrogenic modulation of spatial memory, and 3) To investigate whether estrogen modulates cholinergic function and spatial memory via activation of the ERa receptor. Ovariectomized female mice will receive one session of training in a spatial water maze task requiring them to use extramaze cues to locate a hidden escape platform. Immediately afterward, they wilt be injected with estrogen, scopolamine, or a combination of both. Twenty-four hours later, mice will receive a retention test. One week later, the mice will again be injected with estrogen and scopolamine and then sacraficed 24 hours later for analysis of choline acetyltransferase (CHAT) activity in the hippocampus and frontoparietal cortex. In Experiment 1, we will examine the ability of post-training estrogen injections to enhance spatial memory and augment cholinergic function in the presence of the cholinergic antagonist scopolamine. Because we hypothesize that the locus of estrogenic-cholinergic interaction is the basal forebrain, Experiment 2 will test the ability of estrogen to enhance memory using mice in whom basal forebrain cholinergic neurons were selectively destroyed using the toxin saporin, which is linked to antibodies raised against the mouse low-affinity nerve growth factor receptor, p75. Finally, in Experiment 3 we will examine whether estrogen modulates spatial memory and cholinergic function via activation of the ERa receptor. Findings from the proposed studies will lay a foundation to elucidate the mechanisms by which estrogen influences cholinergic modulation of memory. If estrogen improves memory by modulating basal forebrain cholinergic function, then this work may have significant implications for the treatment of Alzheimer's disease, for which anticholinesterases are largely ineffective.